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Trifluoroacetic acid → 2-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(2,6-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazole

HRID 579351
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 579351
CCN(C(C)C)C(C)C.Br[C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)=[CH:18][C:17]=2[O:28][CH3:29])=[N:14][N:15]=1.[CH2:30]1[C:33]2([CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]2)[CH2:32][NH:31]1.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1.C(Cl)Cl.CO>[CH3:29][O:28][C:17]1[CH:18]=[C:19]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[CH:20]=[CH:21][C:16]=1[C:13]1[S:12][C:11]([N:31]2[CH2:32][C:33]3([CH2:38][CH2:37][CH2:36][NH:35][CH2:34]3)[CH2:30]2)=[N:15][N:14]=1
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

8

Edukt 4

HCID 6422Trifluoroacetic acid2×HCID 81531DiisopropylethylamineHCID 24820496Tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylateHCID 867271732-bromo-5-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole

Produkt 1

HCID 867271722-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(2,6-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazole

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 887MethanolLösungsmittelHCID 6344DichloromethaneLösungsmittelHCID 13387N-methyl-2-pyrrolidoneLösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

DIPEA (116 μL, 0.666 mmol) was added to a stirred suspension of 2-bromo-5-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole (78 mg, 0.222 mmol) and tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate (acetic acid salt, 127 mg, 0.444 mmol) in NMP (444 μL) and the mixture was heated at 120° C. for 3 hours. The reaction mixture was diluted with DCM (10 mL), washed with saturated NaHCO3(aq) (10 mL), and the organic phase was separated. TFA (342 μL, 4.44 mmol) was added and the resulting solution was stirred at room temperature for 18 hours. A further 1 mL TFA was added and the reaction mixture was warmed to 35° C. and stirred for 48 hours. The reaction mixture was loaded onto a 1 g SCX cartridge (pre-wet with MeOH) and the cartridge was washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the crude product as a brown oil. The crude material was purified by UV directed preparative HPLC under acidic conditions (TFA modified) and the product containing fractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10 mL) and flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound a white foam-like solid (40.5 mg, 46% yield). LC-MS: Rt 0.83 min; MS m/z 397.1 [M+H]+ [Method D], 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 8.06 (d, J=8.08 Hz, 1H), 7.99 (s, 1H), 7.37 (d, J=1.52 Hz, 1H), 7.29 (dd, J=8.08, 1.52 Hz, 1H), 4.00 (s, 3H), 3.88 (s, 3H), 3.81 (d, J=7.58 Hz, 2H), 3.74 (d, J=7.58 Hz, 2H), 2.82 (s, 2H), 2.60 (t, J=5.05 Hz, 2H), 1.73 (t, J=5.56 Hz, 2H), 1.41 (quin, J=5.56 Hz, 2H).

Aufarbeitung

  1. washwashed with saturated NaHCO3(aq) (10 mL)
  2. customthe organic phase was separated
  3. temperaturethe reaction mixture was warmed to 35° C.
  4. stirringstirred for 48 hours
  5. washthe cartridge was washed with MeOH (10 mL)
  6. customthen flushed with 7M NH3 in MeOH (10 mL)
  7. customThe MeOH/NH3 was removed in vacuo
  8. customto afford the crude product as a brown oil
  9. customThe crude material was purified by UV
  10. additionthe product containing fractions
  11. washThe cartridge was washed with MeOH (10 mL)
  12. customflushed with 7M NH3 in MeOH (10 mL)
  13. customThe MeOH/NH3 was removed in vacuo

Quellen und Nachweise

ORD-Eintrag
ord-d8a41dd90f24401f85af582390e8000f
Quelldatensatz
uspto-grants-2015_05
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US09040712B2

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